This application for an Independent Scientist Award (K02) requests support to develop an integrated program of cocaine research. Cocaine abuse persists as a leading public health problem in the country and basic research can contribute to diminishing the national burden. A systematic approach to investigating the molecular targets of cocaine and consequences of cocaine abuse to the brain will provide information needed for the development of novel and effective treatments of cocaine abuse. The goals of the laboratory are to consolidate chemical, biochemical, imaging and behavioral approaches to cocaine research and provide a bridge for clinical applications. Studies are proposed to investigate the molecular targets of cocaine in nonhuman primate and human brain with a view to identifying potential sites for drug therapies. Although current evidence converges on basal ganglia doparnine systems as primary contributors to the reinforcing properties of cocaine, the profuse sequelae produced by cocaine supports the need to probe other neurochemical targets of cocaine in discrete brain regions. The investigator will continue a productive collaborative program to develop novel cocaine substitutes or antagonists and utilize neurochemical, behavioral and biochemical techniques to evaluate the suitability of these drugs for the treatment of cocaine abuse. She will develop and utilize ligands for PET or SPECT imaging of brain to identify long-acting cocafne substitutes and to quantify the targets of cocaine in living brain tissue. This pragmatic and integrated approach will provide fundamental information on the neurobiology of cocaine with direct relevance to clinical applications.